Process for the production of tert-butyl (E)-(6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl](4R,6S)-2, 2-dimethyl[1, 3]dioxan-4-yl)acetate

ABSTRACT

The invention concerns a process for the manufacture of tert-butyl (E)-(6-[2-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl)-(4R, 6S)-2,2-dimethyl(1,3-dioxan-4-yl) acetate, the novel starting material used in said process and the use of the process in the manufacture of a pharmaceutical.

This is a Continuation of copending Application No. 09/913,539, filedDec. 7. 2001; which is a PCT National Phase Application of PCT/00/00481filed Feb. 15, 2000, which claims priority to GB application No.9903472.0 filed Feb. 17, 1999. Each listed U.S. Patents and/orapplication is entirely incorporated herein by reference in itsentirety.

This invention concerns a novel chemical process, and more particularlyit concerns a novel chemical process for the manufacture of tert-butyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2dimethyl[1,3]dioxan-4-yl)acetateof formula I,

(hereinafter referred to as BEM) which is useful, for example, as achemical intermediate in the production of a pharmaceutical useful inthe treatment of, inter alia, hypercholesterolemia, hyperlipoproteinemiaand atherosclerosis. The invention further includes the novel startingmaterial used in said process and the use of the process in themanufacture of an HMG CoA reductase inhibitor.

In European Patent Application, Publication No. (EPA) 0521471 isdisclosed(E)-7-[4(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5dihydroxyhept6-enoic acid and its sodium salt and calcium salt (illustrated below)

(hereinafter referred to collectively as “The Agent”) as inibitors ofHMG CoA reductase. The Agent is obtained therein via reduction of methyl7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-amino)pyrimidin-5-yl-(3R)-3-hydroxy-5-oxo-(E)-heptenoateand subsequent processing. However the Agent may be obtained from BEM bytreatment with acid (to cleave the acetonide protecting group) followedby base (to cleave the ester) and (as described in EPA 0521471)conversion of the initially formed salt to the free acid or the calciumsalt.

We have now discovered a useful and advantageous process for preparingBEM.

According to the invention there is provided a process for preparing BEM(formula I) which comprises reaction of diphenyl[4-(4-fluoropheny)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-ylmethyl]phosphine oxide of formula III

(hereinafter referred to as DPPO) with tert-butyl2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl}acetate of formula II

(hereinafter referred to as BFA) in the presence of a strong base.

The process is carried out in a suitable solvent, or mixture of solventsfor example, ethereal or aromatic solvents or mixtures thereof.Particularly suitable solvents include, for example, tetrahydrofuran(THF), dimethoxyethane and toluene, or mixtures thereof. Particularlypreferred solvents include, for example, THF and THF and toluene.

Suitable bases for use in the process include, for example, amide bases,alkyl metals and metal hydrides. Particular bases include, for example,sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide,lithium bis(trimethysilyl)amide, butyllithium and sodium hydride. Aparticularly preferred base is, for example, sodiumbis(trimethylsilyl)amide (NaHMDS).

The reaction may be carried out at a temperature in the range of, forexample, −20° C. to −90° C., such as −40° C. to −90° C., for example−40° C. to −80° C. A convenient tempreture at which to carry out thereaction is, for example, that of a mixture of acetone and solid carbondioxide (about −75° C.).

The process is advantageously carried out with 1.0 to 1.2 equivalents ofbase (per equivalent of DPPO), such as 1.05 to 1.2 equivalents andpreferably 1.05 to 1.12 equivalents. Although BFA can be present inlarge excess, it is convenient to use 1.0 to 1.35 equivalents (perequivalent of DPPO), and preferably 1.05 to 1.3 equivalents, especially1.05 to 1.15 equivalents.

The process of the invention provides significantly improved yields andquality of product by comparison to when a corresponding dialkylphosphonate (—PO(Oalkyl)₂) starting material is used instead of DPPO.

The starting material, DPPO, which is a further aspect of the presentinvention, may be obtained as described in the Examples hereinafter,starting from an alkyl2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-carboxylate, forexample the methyl ester which may be obtained as described in JapanesePatent Application No. 06-256318, or the ethyl ester which may beobtained as described in EPA 0521471. BFA may be obtained as describedin EPA 0319847 (Example 6).

A further aspect of the present invention is a process for themanufacture of a compound of the formula IV

in which R¹ is hydrogen or a pharmaceutically acceptable cation, whichcomprises;

(1) reaction of DPPO with BFA in the presence of a strong base (asdescribed above) to give BEM;

(2) cleavage of the dihydroxy (acetonide) protecting group (for exampleby acid hydrolysis, such as by using HCl in THF or acetonitrile); and

(3) cleavage of the tert-butyl ester group under basic conditions toform a compound of the formula IV in which R¹ is a pharmaceuticallyacceptable cation (for example by using a solution of a metallichydroxide in a polar solvent, such as using aqueous sodium hydroxide inethanol or acetonitrile to form the sodium salt);

optionally followed by neutralisation to give a compound of the formulaIV in which R¹ is hydrogen;

and/or optionally followed by conversion to another compound of theformula IV in which R¹ is a pharmaceutically acceptable cation (forexample conversion of the sodium salt to the calcium salt by treatmentwith a water soluble calcium salt (such as calcium chloride) underaqueous conditions).

Suitable conditions for steps (2), (3) and the subsequent optional stepsare analogous to, or the same as, those disclosed in EPA 0521471 and/orEPA 0319847, which are hereby incorporated herein by reference. Toobtain the calcium salt of the compound of formula IV, as illustrated onpage 1, preferably steps (2), (3) and conversion to the calcium salt viathe methylamine salt are carried out as described in Example 7, whichsteps form a further aspect of the invention.

It will be appreciated that, in the processes described above, BFA mayreplaced by a compound of the general formula V

in which P³ is a carboxylic acid protecting group, for example(1-8C)alkyl (such as 1-4C)alkyl), and P¹ and P² are alcohol protectinggroups, or P¹ and P² taken together is a 1 , 3-diol protecting group,such as those described in EPA 0319845 and GB 2244705 which are includedherein by reference. For example, in some preferred embodiments, the1,3-dial protecting groups can be

where R¹ and R² are independently (1-4C)alkyl or R¹ and R^(2,) takentogether with the carbon atom to which they are attached, form acyclopentyl. cyclohexyl or cycloheptyl ring. Reaction of a compound ofthe formula V with a compound of the formula III forms a compound of theformula VI

The compound of the formula VI may be converted to the Agent by cleavageof the alcohol or diol protecting groups and conversion of the COOP³ toa COOH group or a pharmaceutically acceptable salt thereof. Such generalprocesses form further features of the present invention.

The invention if further illustrated, but not limited by the followingExamples.

Preparation 1

Preparation of DPPO

A stirred mixture of methyl4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-carboxylate(12.0 g) in toluene (55 ml) was cooled to −10° C. and diisobutylaluminium hydride (50 ml of a 1.5M solution in toluene) was added overtwo hours maintaining the temperature below 0° C. After addition, themixture was stirred for 30 minutes at 0° C. Methanol (0.64 ml) was addedto the mixture maintaining the temperature at 0° C. The mixture was thenadded over two hours to a stirred mixture of concentrated hydrochloricacid (23.3 ml), water (40.5 ml) and acetonitrile (24 ml) at 40° C.,maintaining the temperature of the mixture at 40° C. After addition, themixture was stirred at 40° C. for a further 30 minutes and then purgedwith nitrogen (to remove any isobutane). The mixture was cooled to 20°C. and allowed to stand for 20 minutes. The organic phase was separatedand washed with a mixture of concentrated hydrochloric acid (0.7 ml) andwater (30 ml). Acetonitrile (24 ml) was added to the organic phase andthe mixture washed with a solution of sodium bicarbonate (0.038 g) inwater (120 ml).

The organic phase was heated to 40° C., and then from 40° C. to 80° C.using a nitrogen purge. The mixture was concentrated by distillation atatmospheric pressure, collecting 54 ml of distillate. Acetonitrile (24ml) was added to the concentrated solution and phosphorus tribromide(1.2 ml) was added with stirring, maintaining the temperature of themixture at 20° C. After addition, the mixture was stirred at 20° C. for30 minutes. The mixture was added to water (36 ml) over 30 minutesmaintaining the temperature at 20° C. The mixture was stirred for 5minutes and the organic phase separated. The organic phase was washedwith a solution of sodium bicarbonate (0.027 g) in water (36 ml),followed by water (36 ml). The organic phase was distilled under reducedpressure until 29 ml of distillates was collected. The mixture wascooled to 60° C. and ethyl diphenylphosphinite (7.47 ml) was added. Themixture was stirred at 60° C. for 3 hours, then heated to reflux.Toluene (40 ml) was added and the mixture cooled to 0° C. over 2 hours.The product was collected by filtration, washed with cold toluene (10ml) and dried under vacuum at 50° C. to give DPPO (14.66 g); ¹HNMR(CDCl₃, 270 MHz): 7.42 [m, 10H, P(C₆H₅)₂], 7.12 [m, 2H, Ar—H], 6.92 [m,[d,2H, CH₂P], 3.51, 3.46 (2× s, 6H, NCH, SO₂CH₃], 3.43 [hept., 1H,CH(CH₃)₂],1.25[d, 6H, CH(CH₃)₂],1.25[d,6H, CH(CH₃)₂]

Methyl4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino)pyrimidine-5-carboxylatewas prepared as follows:

A mixture of methyl2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-carboxylate (19.0g), sodium tert-pentoxide (22.95 g) and dimethoxyethane (190 ml) wasstirred for 30 minutes at 25° C. The stirred mixture was cooled to −10°C. and methanesulfonyl chloride (8.4 ml) was added dropwise, maintainingthe temperature of the mixture at −5° C. After 20 minutes, dimethylsulfate (8.1 ml) was added and the mixture allowed to warm to 25° C. Themixture was stirred for one hour at 25° C. and a solution of sodiumtert-pentoxide (1.91 g) in dimethoxyethane (10 ml) added. The mixturewas stirred for one hour at 25° C. A solution of sodium chloride (13.3g) in water (133 ml) was added and the mixture was stirred for 10minutes at 25° C. The mixture was allowed to settle for 15 minutes andthe lower aqueous phase was separated and discarded. Water (38 ml) wasadded to the remaining mixture and the mixture was stirred for 30minutes at 25° C. The mixture was then heated to obtain a completesolution. The mixture was cooled slowly to 25° C. over one hour. Themixture was cooled to 0° C., stirred for one hour, and the suspendedsolid collected by filtration. The solid was washed with cold (0° C.)solution of 50:50 water/dimethoxyethane (20 ml). The solid was driedunder vacuum at 60° C. to give methyl4-(4-fluorophenyl)-6isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-carboxylate(19.35 g); ¹HNMR (270 MHz, CDCl₃): 7.69 (m,2H), 7.14 (m,2H), 3.71, 3.60,3.51(3× s, 9H), 3.20 (m, 1.(d,6H).

EXAMPLE 1

A mixture of DPPO (19.17 g) and THF (227 ml) were warmed briefly to 40°C. until a clear solution had formed then inerted by the sequentialapplication of vacuum and nitrogen (5 cycles). The mixture was immersedin an acetone/CO₂ bath cooling the contents to −75° C. Sodiumbis(trimethylsilyl)amide (37.4 ml of 1.0M solution in THF) was added tothe reaction mixture over 10 minutes from a pressure equalising droppingfunnel maintaining the temperature below −74° C. and forming a redsolution of the anion. THF (10 ml) was rinsed through the droppingfunnel into the mixture and the mixture stirred a further 1 hour at −76°C. forming a red suspension. BFA (80 ml of ˜13.5% w/w toluene solution)was added in portions to the suspension over 20 minutes from a pressureequalising dropping funnel maintaining the temperature below −73° C.Toluene (20 ml) was rinised through the dropping funnel into the mixtureand the mixture stirred a further 15 minutes at −76° C. The chillingbath was lowered and the suspension allowed to warm to 10° C. over 1.5hours. Glacial acetic acid (3.21 g) in water (15 g) was added in oneportion raising the temperature to 18° C. and dissolving all solids andthe mixture was stirred a further 5 minutes.

The mixture was concentrated by distillation at atmospheric pressure(jacket 110° C.) to a temperature of 94° C. collecting a total of 274 mldistillates. The concentrated mixture was cooled to 40° C., water (40ml) was added and the mixture stirred for 5 minutes then allowed tosettle for 15 minutes. The lower aqueous phase was discarded. Sodiumhydrogen carbonate (2.99 g) in water (40 ml) was added and the mixturestirred for 5 minutes then allowed to settle for 15 minutes. The loweraqueous phase was discarded. Water (30 ml) was added and the mixturestirred for 5 minutes then allowed to settle for 15 minutes. The loweraqueous phase was discarded.

The organic phase was transferred to a distillation apparatus withtoluene (20 ml) and concentrated by distillation at atmospheric pressure(jacket 125-130° C.) to a temperature of 116° C. collecting 85 mldistillates. Vacuum was applied (400-500 mbar) and a further 16.5 mldistillates collected to a temperature of 111° C. The vacuum wasreleased and the concentrated mixture allowed to cool to 80° C. WarmMeOH (140 ml, 50° C.) was added with rapid stirring and the batchallowed to self-cool to 20° C. over 30 minutes during which time a solidwas deposited. The suspension was further cooled to 2° C. for 30 minutesthen the solid was collected by filtration on a sinter and pulled as dryas possible. The solid was washed with cold MeOH (60 ml, 2° C.) andagain pulled as dry as possible then transferred to a vacuum oven anddried overnight (50° C., 200 mbar); giving BEM (14.01 g, 67.7%).

¹H NMR (CDCl₃, 270 MHz)7.65 [m, 2H, Ar—H], 7.09 [m, 2H, Ar—H], 6.52 [dd,1H, ArCH═CH], 3.57, 3.50 [2× s, 6H, NCH₃, SO₂CH₃], 3.38 [hept., 1H,Ar—CHMe₂],2.45, 2.30[2x dd, 2H, CH₂CO₂tBu], 1.55, 1.13 [dt, dd, 2H,acetonide CH₂], 1.50, 1.40 [2 x s, 6H,acetonide C(CH₃)₂], 1.45 [s, 9H,CO₂C(CH₃)₃], 1.27 [dd 6H, ArCH(CH₃)₂]

EXAMPLES 2-6

The procedure as described in Example 1 was carried out using the ratiosof reactants and the temperatures given in Table 1. There was thusobtained BEM in the yields given.

TABLE 1 Wt DPPO Temp. (° C.) Eq. NaHMDS Eq. BFA BEM Yield 10.00 g −751.12 1.20 69.2% 18.12 g −75 1.12 1.20 69.6% 12.08 g −75 1.06 1.26 72.8%19.17 g −40 1.05 1.06 56.7% 9.57 g −90 1.05 1.10 72.0% 9.57 g −60 1.051.10 70.1%

EXAMPLE 7

A mixture of BEM (5.0 g) and acetonitrile (35 ml) was stirred under aninert atmosphere at 40° C. 0.02M hydrochloric acid (9.5 ml) was addedover 30 minutes to the resultant solution, maintaining the temperatureat 35° C. to 42° C. The mixture was stirred at 40° C. for 3 hours thencooled to 25° C. 1.0M sodium hydroxide solution (9.5 ml) was added withstirring at 25° C. and the mixture was stirred for an additional onehour at 25° C. Sodium chloride (4.7 g) was added and the mixture wascooled to −5° C. over one hour. Sufficient of a solution of 1Mhydrochloric acid (9.5 ml) and sodium chloride (2.4 g) was added at −5°C. to achieve a pH of 3.4 to 4.0 and the mixture stirred at thistemperature for 5 minutes. The mixture was allowed to settle for 10minutes at −5° C. to give two layers. The lower layer was separated anddiscarded. Acetonitrile (65 ml) at −5° C. was added to the remainingsolution and the mixture was filtered through a filter agent. 40%methylamine solution in water (1.1 ml) was added at −5° C. and themixture was warmed to 30° C. over 40 minutes and maintained at thistemperature for 90 minutes. The mixture was then cooled to 0° C. over 40minutes and maintained at this temperature for 90 minutes. The resultantsolid was collected by filtration and washed with acetonitrile (2×12ml). The solid, which is the methylamine salt of the compound of formulaIV (R¹═MeNH₃ ⁺), was dried under vacuum at 35° C. (3.87 g). 8% w/waqueous sodium hydroxide (5.44 ml) was added to a stirred mixture of themethylamine salt (6.0 g) in degassed water (30 ml) at 20° C. and themixture was stirred for one hour. The mixture was filtered andconcentrated under reduccd pressure at 40° C. until 24 ml of distillatecollected. Water (24 ml) was added and the mixture again concentratedunder reduced pressure at 40° C. until 24 ml of distillate collected.Water (30 ml) was added and a solution of calcium chloride dihydrate(1.03 g) in water (6 ml) was added dropwise at 20° C. The mixture wasstirred for 45 minutes and the resultant solid filtered. The solid waswashed with water (36 ml) and dried under vacuum at 40° C. to give thecalcium salt of(E)-7-[4-(4-flurorophenyl)-6-isopropyl-2-(methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid.

What is claimed is:
 1. A compound of the Formula VI

wherein P¹ and P² are alcohol protecting groups, or P¹ and P², takentogether, form a 1,3-diol protecting group; and P³ is a carboxylic acidprotecting group.
 2. The compound of claim 1, wherein P¹ and P², takentogether, form

where R¹ and R² are independently (1-4C)alkyl, or R¹ and R², takentogether with the carbon atom to which they are attached, form acyclopentyl, cyclohexyl or cycloheptyl ring; and P³ is (1-4C)alkyl or ametal cation.
 3. A process for the manufacture of a compound of theFormula IV

in which R¹ is hydrogen or a pharmaceutically acceptable cation whichcomprises (1) cleavage of the P¹ and P² alcohol or 1,3-diol protectinggroups from a compound of Formula VI; (2) cleavage of the P³ carboxylicacid protecting group from the product of step (1) to form a compound ofthe Formula IV in which R¹ is a pharmaceutically acceptable cation;optionally followed by neutralization to give a compound of the FormulaIV in which R¹ is hydrogen; and/or optionally followed by conversion toanother compound of the Formula IV which R¹ is a pharmaceuticallyacceptable cation.
 4. A process for the manufacture of a compound of theformula III

which comprises: (1) reaction of an alkyl4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)axnino]pyrimidine5carboxylatewith a reducing agent; (2) reaction of the product of step (1) with ahalogenating agent; (3) reaction of the product of step (2) with analkyldiarylphosphinite.
 5. A process as claimed in claim 4 wherein thereducing agent is diisobutylaluminum hydride.
 6. A process as claimed inclaim 4 wherein the halogenating agent is phosphorus tribromide.
 7. Aprocess as claimed in claim 4 wherein the alkyl diarylphosphinite isethyl diphenylphosphinite.
 8. A process as claimed in claim 4 where thealkyl4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-carboxylateis methyl4(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5carboxylate.9. A process for the manufacture of methyl4-(4-fluorophenyl)-6-isopropyl-2-[(methyl(methylsulfonyl)amino)pyrimidine-5-carboxylatewhich comprises: (1) reaction of methyl2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-carboxylate withmethanesulfonyl chloride in the presence of strong base; and (2)reaction of the product of step (1) with a methylating agent in thepresence of strong base.
 10. A process as claimed in claim 9, whereinthe methylating agent is dimethyl sulfate.
 11. A process as claimed inclaim 9, wherein the strong base is sodium tert-pentoxide.